The first carbapenem antibiotic to be discovered was thienamycin, isolated from naturally occurring streptomyces cattleya by Merck Co., U.S.A. in 1976.
Since thienamycin is highly chemically unstable despite superior pharmacological effects, it has not been developed into medicines. Many attempts have been made to overcome the chemical instability of thienamycin while maintaining the pharmacological effects of thienamycin. For example, imipenem, which is a novel thienamycin derivative synthesized by Merck Co., is prepared by modifying the amine group of thienamycin into an N-formimidoyl group. Imipenem is a new concept antibiotic with ensured stability. Imipenem has been widely used as a therapeutic agent to date. Imipenem as a carbapenem antibiotic is the first available compound among new type beta-lactam antibiotics possessing a carbapenem ring system, and shows high stability even in the presence of beta-lactamase. In addition, imipenem exhibits an extremely broad spectrum of antibiotic activity against gram-positive and gram-negative aerobic and anaerobic species. Imipenem is prepared only by chemical total synthetic, unlike conventional cephalosporin antibiotics.
The first industrial synthetic of imipenem was reported in 1981. Since 1989, improved synthetic processes of imipenem have been suggested.
U.S. Pat. No. 4,292,436 discloses a process for preparing in-situ imipenem monohydrate by activating a bicyclic keto ester, reacting the activated ester with an amine-protected N-formimidoyl-2-aminoethanethiol compound, followed by catalytic hydrogenation using platinum oxide as a catalyst to remove the 2-carboxyl and the amine protecting groups without isolation of any intermediate, as depicted in Reaction Scheme 1 below:

wherein R is hydrogen or a protecting group; and X is a leaving group.
However, this process has the disadvantages that the imipenem is prepared from the bicyclic keto ester in a yield as low as 35% and the process further involves four stages in the preparation of the protected N-formimidoyl 2-aminoethanethiol compound. In addition, another disadvantage of the process is that large excesses of water (660-fold amount of the starting material) and solvents are necessary for extraction upon washing after the N-formimidoyl 2-aminoethanethiol compound is introduced, resulting in an economical disadvantage.
On the other hand, U.S. Pat. Nos. 4,845,261 and 4,894,450 disclose a novel process for continuously preparing imipenem from a bicyclic keto ester via four stages without isolation and purification of any intermediates. The procedure of the process is depicted in Reaction Scheme 2 below:

wherein R, is a p-nitrobenzyl group.
As depicted in Reaction Scheme 1, since the process consisting of four stages proceeds in-situ without undergoing any separation and purification, the final product inevitably contains large amounts of impurities, which makes the separation and purification of the final product difficult. In addition, the process is accompanied by the use of costly bis(dichlorophenyl)phosphorochloridate in order to activate the bicyclic keto ester precursor.
Since expensive N-ethylpyrrolidinone used as a reaction solvent in Reaction Scheme 2 is a highly polar organic solvent, it is difficult to remove the solvent from the resulting aqueous solution after completion of the reaction. Further, the excessive use of the reaction solvent (200-fold amount of the starting material) creates an economic burden in the industrialization of the process.
U.S. Pat. No. 4,373,772 proposes a semi-synthetic process of imipenem monohydrate using thienamycin isolated from streptomyces cattleya as a starting material. The overall procedure of this process is depicted in Reaction Scheme 3 below:

As depicted in Reaction Scheme 3, however, since the chemically unstable thienamycin is obtained in a small amount from the microorganism, the process is disadvantageous in terms of poor economic efficiency. In addition, the use of an excess of water (214-fold amount of the starting material) as a reaction solvent causes difficulties in reaction, separation, and purification. Furthermore, the process has the disadvantage that 5% or more of dimer bis-thienamycin formamidine is formed as an undesired reaction by-product along with the desired product imipenem.
Dr. Ranbaxy filed an international PCT application (WO 02/36594) relating to a process for preparing imipenem. This process is similar to the process of Merck Co., except that a mixed solvent of tetrahydrofuran and costly 1,3-dimethyl-3,4,5,6-tetrahydro-(2H)-pyrimidinone is used as a reaction solvent. However, the publication does not refer to a hydrogenation catalyst. In addition, the final product imipenem in a crystalline form is prepared in a very low yield of 23% from a bicyclic keto ester as a starting material by adsorption chromatography.